Hanley, Gillian E.

Abstract Background Opportunistic bilateral salpingectomy (OBS), the removal of fallopian tubes during hysterectomy or instead of tubal ligation, is recommended to reduce ovarian cancer risk. However, data on the effectiveness of prophylactic OBS is limited. Methods This population-based retrospective cohort included individuals aged 18–80 in Ontario, Canada, who underwent OBS or comparator surgeries (hysterectomy with ovarian and tubal conservation or tubal ligation) from 2011 to 2023. Individuals with gynecologic cancer before or within six months of surgery were excluded. Hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards regression. Sensitivity analyses varied the time between surgery and cancer diagnosis to account for pre-existing serous tubal intraepithelial carcinomas. Results Among 196,839 individuals, 57,941 underwent OBS and 138,898 underwent comparator surgeries. 142 epithelial ovarian cancers were diagnosed (19 in the OBS group and 123 in the comparator surgery group). OBS was associated with reduced risk of any ovarian carcinoma, with an adjusted hazard ratio (aHR) of 0.60 (95% CI, 0.36 to 0.98). For serous ovarian carcinoma (high- and low-grade combined due to missing grade data), the aHR was 0.47 (95% CI, 0.22 to 0.99). Sensitivity analyses with 12- and 18-month intervals showed aHRs of 0.59 (95% CI, 0.35 to 0.99) and 0.60 (95% CI, 0.35 to 1.01) for all ovarian carcinomas, and 0.49 (95% CI, 0.23 to 1.01) and 0.47 (95% CI, 0.22 to 0.99) for serous ovarian carcinoma, respectively. Conclusions OBS was associated with reduced risk of ovarian carcinoma, supporting its role as a primary prevention strategy.

This cohort study evaluates the reduction in risk of high-grade serous carcinoma among women undergoing opportunistic bilateral salpingectomy in Canada.

Abstract Introduction: The purpose of this study is to evaluate the effectiveness of opportunistic salpingectomy (OS), a procedure that aims to remove only the fallopian tubes of general population risk women, for the prevention of epithelial ovarian cancer. Currently, the method of prevention for individuals at high risk of ovarian cancer involves a bilateral salpingo-oophorectomy (BSO), a procedure that removes both the fallopian tubes and ovaries. However, this procedure is not recommended for individuals of the general population, who make up about 80% of ovarian cancers, due to negative health implications to the cardiovascular and skeletal systems because of surgically induced menopause. The effectiveness of the OS in preventing ovarian cancers and how the procedure impacts the histotype distribution of ovarian cancers remains unknown. Study Methods: This study uses a population-based approach and a case-based approach to determine the effectiveness of OS and its impact on histotype distribution, respectively. For the population-based analysis, we will search through clinical databases to acquire cases of individuals who have had an OS and a tumor. A control population who have their fallopian tubes in-tact will also be acquired. A cox-proportional hazard analysis will be performed to determine the effectiveness of the procedure. Using pathological records, the case-based ascertainment of tumors from individuals who have had an OS will be selected and reviewed for histotype confirmation. Fallopian tubes of these patients will also be reviewed for precursor lesions. This cohort will be compared to a historical histotype distribution of ovarian cancers. Results: For the population-based approach, we have to date, identified less than five serous ovarian cancers in individuals who have had an OS (n=40, 477). A comparator surgery was used as a control and showed 21 cancers. For the case-based approach, we have partnered with 23 collaborating institutions from around the world to identify tumors in individuals who have had an OS. We have identified 26 epithelial ovarian cancers, with the most lethal gynecological histotype, high grade serous carcinoma (HGSC), accounting for 23.1% of the total proportion of epithelial ovarian cancer cases (n=6/26). This is significantly less than the historical histotype distribution of HGSC, which is 69.3% (Fisher’s exact test, p<0.0001). One HGSC case had a precursor lesion called a serous tubal intraepithelial carcinoma (STIC) while reviewing fallopian tubes of this individual. TP53 mutation analysis on one HGSC tumor sample showed a frameshift mutation in TP53 (c229fs) with the tumor and the corresponding STIC staining negative for p53 protein expression by immunohistochemistry. Conclusion: This evidence demonstrates the effectiveness of opportunistic salpingectomy for the prevention of ovarian cancer and shows a histotype distribution shift, with the most lethal gynecological malignancy having a significant reduction in cases following the procedure. Citation Format: Ramlogan Sowamber, Alice J. Mei, Paramdeep Kaur, Julianne McLeod, Emily McKay, Alex Lukey, Jamie Bakkum-Gamez, Natalia Buza, Paul Cohen, Kyle Devins, Rhonda Farrell, Christine Garcia, Blake Gilks, Ellen Goode, Anjelica Hodgson, Brooke Howitt, Pei Hui, Jutta Huvila, Anthony Karnezis, Kianoosh Keyhanian, Mary Kinloch, Martin Köbel, Felix KF. Kommoss, Lawrence Kushi, Janice S. Kwon, Kara Long-Roche, Anais Malpica, Jessica N. McAlpine, Dianne Miller, Esther Oliva, Andrea Palicelli, Aleksandra Paliga, Carlos Parra-Herran, Celeste Leigh Pearce, Sharnel Perera, Jurgen M. Piek, Haiyan Qiu, Joseph Rabban, Robert Rome, Miranda Steenbeek, Rebecca Stone, Aline Talhouk, Kristin M. Tischer, Britton Trabert, Penelope M. Webb, John R. Zalcberg, Gillian E. Hanley, David G. Huntsman. Evaluating the effectiveness of opportunistic salpingectomy (OS) for the prevention of epithelial ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B045.

BACKGROUND Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive 10 or more years after standard treatment. METHODS We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared with mid-term (MTS; 5–7.99 years; n = 433) and short-term survivors (STS; 2–4.99 years; n = 416). Primary tumor samples were immunostained and scored for intraepithelial and intrastromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1 + cells, and PD-L1 + cells) and epithelial content. RESULTS Positive associations with LTS compared with STS were seen for 9 of 10 immune-cell subsets. In particular, the combination of intraepithelial CD8 + T cells and intrastromal B cells showed near 5-fold increased odds of LTS compared with STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype. CONCLUSION The tumor microenvironment of HGSC LTS is distinguished by the intersection of T and B cell coinfiltration, high epithelial content, and C4/differentiated molecular subtype, features which may inspire new approaches to immunotherapy. FUNDING Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada’s Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; Medical Research Council (MRC); National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.

Abstract Background: Ovarian cancer is the deadliest gynecologic cancer. Standard treatments for advanced stage high-grade serous ovarian cancer, the most common type, include (1) primary cytoreductive surgery (PCS) followed by adjuvant chemotherapy or (2) neoadjuvant chemotherapy (NACT) with interval debulking surgery. Patients in whom PCS is unlikely to yield optimal cytoreduction to no visible residual disease (R0) or who have medical contraindications to PCS are recommended to undergo NACT. Previous studies on associations between environmental factors and risk of any macroscopic residual disease have yielded inconsistent results. We aimed to (1) comprehensively examine the associations between demographic, lifestyle and reproductive factors and risk of residual disease after PCS; and (2) develop and internally validate a risk prediction model based on these factors. Methods: We used pooled data on 3,492 women who had PCS following a diagnosis with advanced stage high-grade serous ovarian, fallopian tube or primary peritoneal cancers from the Ovarian Cancer Association Consortium. Fifteen exposures of interest included age at diagnosis, menopausal status, race/ethnicity, education level, first-degree family history of ovarian cancer, endometriosis, smoking, body mass index, parity, incomplete pregnancy, tubal ligation, use of combined oral contraceptives, depot-medroxyprogesterone acetate, estrogen (ET), and combined estrogen-progestin therapy. We fit logistic regression models to examine each exposure-residual disease association in 80% of the data (n=2,794; random selection of participants). We developed a risk prediction model including the factors with p-values ≤0.2. Area under the receiver operating characteristic curve (AUC) was used to assess the model’s discrimination in the remaining 20% of the data (n=698). Results: Of the 3,492 participants, 2,003 (57%) had residual disease following PCS. Older age at diagnosis was associated with an increased risk of residual disease (OR=1.07 per five years, 95% CI 1.03-1.11). In contrast, a family history of ovarian cancer (OR=0.63, 95% CI 0.42-0.95) or ET use for 5+ years (OR=0.61, 95% CI 0.39-0.96) were associated with achieving R0. These above factors were included in the risk prediction model as were race/ethnicity, personal history of endometriosis, and smoking, whose p-values ≤0.2. The model showed modest performance in the validation set (AUC=0.64). Conclusions: Younger age at diagnosis, family history of ovarian cancer, and long-term ET use were associated with achieving R0 following PCS. Future studies incorporating genetic and clinical factors to improve the risk prediction for residual disease following PCS are warranted. Citation Format: Minh Tung Phung, Andrew Berchuck, Ellen L. Goode, Marc T. Goodman, Gillian E. Hanley, Jean Richardson, Bronwyn Grout, Anne Chase, Cindy McKinnon Deurloo, Beth Y. Karlan, Toon Van Gorp, Keitaro Matsuo, Karen McLean, Malcolm C. Pike, Joellen M. Schildkraut, Kathryn L. Terry, Anna DeFazio, Penelope M. Webb, Paul D. P. Pharoah, Susan J. Ramus, Celeste Leigh Pearce. Environmental factors associated with residual disease after ovarian cancer primary cytoreduction surgery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2248.

Abstract Background: There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects. Methods: This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data. Results: There was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03–1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11–1.54). Conclusions: A higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival. Impact: Given that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.